PROJECT SUMMARY: Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction by age 80, rendering benign prostatic hyperplasia (BPH) the most common proliferative abnormality in humans. LUTS secondary to BPH negatively impact the quality of life of 210 million men globally, accounting for significant life years lost. In this study we propose to clinically evaluate the mechanisms of resistance to 5?-reductase inhibitor, finasteride, one of the more common drugs used to manage BPH and associated LUTS. Ongoing work in our lab has focused on steroid 5?-reductase 2 (SRD5A2, aka: 5?-reductase 2 [5AR2]), the enzyme responsible for prostatic development and growth. Our investigations have revealed that expression of SRD5A2 is variable, and in fact, 30% of men do not express SRD5A2 in prostate tissues. In previous work, we showed that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Our studies indicate that (1) methylation of the SRDA2 is regulated by direct binding of the DNA-methyl transferase 1 (DNMT1) protein to the SRD5A2 promoter; (2) the inflammatory mediators TNF-?, NF-kB, and IL-6 regulate DNMT1 binding and subsequent methylation of the SRD5A2 promoter region; (3) clinical conditions associated with increased inflammation, age, and obesity, are associated with decreased expression of SRD5A via epigenetic modification; (4) in the absence of prostatic SRD5A2, where androgenic pathways are blocked, alternate estrogenic pathways are upregulated, leading to an androgenic-to-estrogenic switch in the prostate gland, thus creating alternate pathways for prostatic growth. Therefore, we hypothesize that absence of SRD5A2 as a result of somatic methylation is directly responsible for lack of sensitivity to 5ARI therapy in men with BPH. To demonstrate the clinical significance of epigenetic changes to SRD5A2 and confirm its role in regulating sensitivity to 5ARI treatment, we propose the following aims: Specific Aim 1: To assess the role of 5-AR2 expression in the development of resistance to 5-ARI therapy. Specific Aim 2: To demonstrate that SRD5A2 methylation turns on estrogen pathways and affects sensitivity to 5ARI therapies in men with BPH. Specific Aim 3: To determine that prostatic inflammation is associated with methylation of SRD5A2 promoter. Our findings have broad implications for the development of predictive biomarker assays that can be used to evaluate resistance to BPH-related therapies and allow clinicians to select alternate therapies for managing the most common proliferative disorder affecting men worldwide.